NO is an environmental pollutant produced as a byproduct of combustion. At extremely high concentrations (generally at or above 1000 ppm), NO is toxic. NO also is a naturally occurring gas that is produced by the endothelium tissue of the respiratory system. In the 1980's, it was discovered by researchers that the endothelium tissue of the human body produced NO, and that NO is an endogenous vasodilator, namely, an agent that widens the internal diameter of blood vessels.
With this discovery, numerous researchers have investigated the use of low concentrations of exogenously inhaled NO to treat various pulmonary diseases in human patients. See e.g., Higenbottam et al., Am. Rev. Resp. Dis. Suppl. 137:107, 1988. It was determined, for example, that primary pulmonary hypertension (PPH) can be treated by inhalation of low concentrations of NO. With respect to pulmonary hypertension, inhaled NO has been found to decrease pulmonary artery pressure (PAP) as well as pulmonary vascular resistance (PVR). The use of inhaled NO for PPH patients was followed by the use of inhaled NO for other respiratory diseases. For example, NO has been investigated for the treatment of patients with increased airway resistance as a result of emphysema, chronic bronchitis, asthma, adult respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease, (COPD). In 1999, the FDA approved the marketing of nitric oxide gas for use with persistent pulmonary hypertension in term and near term newborns. Because the withdrawal of inhaled nitric oxide from the breathing gas of patients with pulmonary hypertension is known to cause a severe and dangerous increase in PVR, referred to as a “rebound effect”, nitric oxide must be delivered to these patients on a continuous basis.
In addition to its effects on pulmonary vasculature, NO may also be introduced as a anti-microbial agent against pathogens via inhalation or by topical application. See e.g., WO 00/30659, U.S. Pat. No. 6,432,077, which are hereby incorporate by reference in their entirety. The application of gaseous nitric oxide to inhibit or kill pathogens is thought to be beneficial given the rise of numerous antibiotic resistant bacteria. For example, patients with pneumonia or tuberculosis may not respond to antibiotics given the rise of antibiotic resistant strains associated with these conditions.
Clinical use of nitric oxide for inhalation has conventionally been limited to low concentration of nitric oxide given the potential toxicity. The toxicity may stem from binding of nitric oxide to hemoglobin that give rise methemoglobin or from the conversion of nitric oxide gas to nitrogen dioxide (NO2). However, to overwhelm pathogenic defense mechanisms to nitric oxide, it is desirable to deliver nitric oxide at a higher concentration (e.g., between 150 ppm to 250 ppm, and even to 400 ppm) than has traditionally been used clinically for inhalation. Thus, a need exists for a delivery method that is effective against combating pathogens and minimizing the risk of toxicity.